Streptococcus pneumoniae is one of Gram-positive encapsulated diplococci. Pneumococcal infection is a leading infectious cause of the high mortality and morbidity worldwide, especially among young children below two years of age and the elderly over sixty years of age. Globally, pneumococcal infection has been estimated to cause about 1.6 million deaths annually, including 1 million children less than five years old. Even though certain vaccines have been applied to prevent the S. pneumoniae infection, the mortality rate caused by this organism is still ranked the highest. The spectrum of the S. pneumoniae-related diseases includes invasive pneumococcal disease (IPD), such as sepsis and meningitis; lower respiratory infections, such as bacterial pneumonia; and upper respiratory infections, such as acute otitis media (AOM) (Tuomanen et al., 1995).
According to the reports of World Health Organization (WHO) in 2005, acute respiratory tract infections were the major cause of death globally, in which the deaths were chiefly attributable to the S. pneumoniae-associated community-acquired pneumonia (CAP). This threatening issue strongly raises the urgency for both diagnosis and prevention. Although the diagnoses of pneumococci have been developed for decades, we still heavily rely on conventional culture methods that are tedious and time-consuming, to proliferate enough bacteria for specific and sensitive detection. Therefore, based on specific DNA amplification and antigen detection, the tests of non-culture samples from sputum, urine, and blood have been continuously developed over time in order to identify pneumococci as the etiological agent of diseases. However, the consequences of those tests were always unsatisfactory in certain applications. For instance, the application of PCR testing for the diagnosis of IPD has ever shown to be insufficiently sensitive when using blood or urinary samples, and poorly specific when using respiratory samples. To overcome the problem of poor specificity when using sputum samples, recently a dual-PCR testing protocol using pneumococcal lytA and ply as targets has been successfully developed and evaluated.
Another disappointing aspect for diagnosis revealed that only one third of pathogens could be recovered from patient's sputum when using conventional culture methods. In addition, the controversial results lack specificity correlated to CAP because nasopharyngeal carriage of pneumococci could also be found in both healthy individuals and inadequate sputum samples. In addition, the etiological pathogens of CAP tested from blood culture and pleural fluid were specific, but the positive rates were lower (<30%) compared to that from sputum sample. For this reason, the development of antigen detection was applied to compensate the drawback of low specificity. Higher sensitivity of the pleural test compared to pleural cultures indicated that antigen detection for pleural samples rather than pleural culture could be a better application for the CAP study of pneumococcal etiology. Also, the detection of BinaxNOW pneumococcal C-polysaccharide in a urine sample with CAP shows unsatisfied result due to its high rate of false positive.
Currently, there are two kinds of vaccines, 23-valent pneumococcal polysaccharide vaccine (PPV23) and 7-valent pneumococcal conjugate vaccine (PCV7), available for general protection against potential IPD-causative pathogen strains. Vaccine PCV7 can target seven serotypes, including 4, 6B, 9V, 14, 18C, 19F, and 23F. Before the introduction of PCV7, the PCV7-targeted 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) were responsible for about 90% of incidence of IPD in young children in the United States and for more than 60% of those in Europe. After PCV7 vaccination, the cases of IPD in children less than 5 years old declined by 56% in 2001 and by 76% in 2004. In contrast, PPV23 vaccination seems to difficultly reach firm conclusions in clinical effectiveness (around 50-70% effective). Although two doses of PCV7 and following one dose of PPV23 were recommended to broaden protection, the effectiveness of vaccines was significant on the protection of those seven PCV7-covered serotypes rather than others. The results suggested that PPV23 seems not necessary as a boost dose for broadening protection.
At least 93 different polysaccharide (PS) capsules of S. pneumoniae have been verified to be specific serotypes, and further classified to be 46 serogroups. Among all pathogenic pneumoncocci worldwide, serotype 14 and serogroup 6 are predominant. In addition, the majority of IPD is generally caused by about 15 serotypes. However, only a few antimicrobial resistant pneumococcal clones could spread fast. The incidence of antimicrobial resistance of pneumococci varies regionally, and is associated with the spectrum of antibiotic use, population density, the indigenous prevalence of resistant strains, ages and time. Although the resistance patterns have been shown to be different around the world, the predominant serotypes commonly identified are 6A/B, 9V, 14, 19A/F, and 23F. Based on epidemiological study, the nasopharyngeal (NP) carriage of predominant pneumococci has been observed in many young children, indicating that NP carriage may play an important role in pneumococcal transmission, especially for antibiotic-resistant strains.
Despite effective reduction of the incidence of IPD caused by vaccine serotypes in both children and adults due to the usage of the current pneumococcal vaccine PCV7, the mortality rate of pneumococcal disease remains high. After the introduction of PCV7 in 2000, nonvaccine serotype 3 was found to be a significant cause for necrotizing pneumonia in children in Utah, whereas a mucoid serotype 3 was usually reported to cause lung abscess in adults. Serotype 19A has been reported the predominant serotype causing IPD all over the world. In Taiwan, complicated pneumococcal pneumonia still remains a clinically intricate problem, and its significant association with the clonal spread of CC320 within serotype 19A was noteworthy recently in Taiwan. Besides pneumococcal serotypes 3 and 19A, other nonvaccine serotypes, including 1, 5, 6A, and 7F, were also common causes for IPD around the world (Grijalva and Pelton, 2011). A second-generation 13-valent pneumococcal conjugate vaccine (PCV13) was therefore developed to address this new global issue of pneumococcal infection in 2010 (Grijalva and Pelton, 2011).
Hemolytic uremic syndrome (HUS), one of the most severe complications of IPD, mainly occurs in children, and it is also associated with hemolytic anemia, thrombocytopenia, and acute renal failure. This disorder, usually occurring in healthy young children, is one of the most common causes of acute renal failure in pediatric patients. Management of the pneumococcal HUS primarily includes an intensive antimicrobial therapy and the dialysis and transfusion of washed RBC, platelets and plasma. Most cases of HUS are reported by an acute gastroenteritis related to Escherichia coli (O157:H7), and often show good prognosis with recovery of renal function. However, the mortality rate of patients with pneumococcal HUS was high in early reports. Of the 14 cases recently reported from USA, 1 (7%) died and 4 (29%) developed chronic kidney disease.
S. pneumoniae encodes many virulence factors, but only the secreted neuraminidase A (NanA) was reported to be attributed to HUS. Neuraminidase cleaves N-acetylneuraminic acid (sialic acid) residues on red blood cells (RBC), platelets and endothelial cells, and the results may lead to the exposure of the Thomsen-Friedenrich antigen (T antigen), and allow the circulating anti-T antigen antibodies to react with the exposed T antigen on cells. The role of neuraminidase(s) in pneumococcal diseases is illustrated based on the fact that pneumococci produce two or three distinct neuraminidases, which are NanA, NanB, and NanC. All three neuraminidases have typically signal peptides for secretion, wherein NanA, unlike NanB and NanC, contains a C-terminal cell surface anchorage domain. NanA and NanB expose host cell surface receptors for pneumococcal adherence by cleaving sialic acid from the glycans and mucin of cell surface, and thereby it promotes the pneumococcal colonization on the upper respiratory tract. In in vivo study, a NanA mutant was cleared from the nasopharynx, trachea, and lungs within 12 hours postinfection, while a NanB mutant persisted but did not increase in either the nasopharynx, trachea, or lungs. However, the role of NanC remains unknown.
The nonvaccine serotypes have been emerging after the use of vaccines. Moreover, nothing worse than the fact that nonvaccine strains usually displayed increase antimicrobial resistance and virulence. This is the reason why the issue of pneumococcal infection remains to be a global public health challenge. Thus, continued efforts to develop new diagnostic methods and to develop vaccines with expanded or universal coverage, such as a universal protein vaccine, are critically required for the better control of the pneumococcal infections.